The present invention relates to an improved process for preparing aromatic ring-fused cyclopentane derivatives. Preferably, the present invention relates to an improved process for preparing indane carboxylates and cyclopentano [b]pyridine derivatives. Advantageously, the present invention relates to an improved process for preparing (+) (1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2carboxylic acid and pharmaceutically acceptable salts thereof and (+) (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof. Such compounds are described in International Application No.: PCT/US94/04603xe2x80x94International Publication No. WO 94/25013 published on Nov. 10, 1994 and in U.S. Pat. No. 5,389,620, as being useful as endothelin receptor antagonists. Also invented are novel intermediates useful in preparing these compounds.
Processes for the preparation of indane carboxylates, specifically (+) (1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2carboxylic acid and (+) (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid have previously been described. In particular a multistep process to prepare (+) (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid in 6% overall yield (not including a racemic separation step) from methyl 3-(prop-1-yloxy)benzoylacetate and a multistep process to prepare (+) (1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid in 2% overall yield (not including a racemic separation step) from methyl 3-(prop-1-yloxy)benzoylacetate is reported in International Publication No. WO 94/25013, published Nov. 10, 1994. The syntheses of these molecules are complicated by the presence of three chiral centers in each compound.
Processes for the preparation of cyclopentano[b]pyridine derivatives have previously been described. In particular, multistep processes to prepare cyclopentano[b]pyridine derivatives, in low over all yield, are reported in U.S. Pat. No. 5,389,620.
Thus, there is a need in the art for an economical method to prepare indane carboxylates and cyclopentano[b]pyridine derivatives, specifically (+) (1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof and (+) (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof.
The numerous advantages of the presently invented process and intermediates will become apparent upon review of the following description.
This invention relates to an improved process for preparing aromatic ring-fused cyclopentane derivatives.
This invention also relates to novel intermediates useful in preparing aromatic ring-fused cyclopentane derivatives.
This invention relates to an improved process for preparing indane carboxylates.
This invention also relates to novel intermediates useful in preparing indane carboxylates.
This invention relates to an improved process for preparing cyclopentano[b]pyridine derivatives.
This invention also relates to novel intermediates useful in preparing cyclopentano[b]pyridine derivatives.
This invention relates to an improved process for preparing (+) (1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof, preferably the ethylene diamine 2:1 salt.
This invention relates to novel intermediates useful in preparing (+) (1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.
This invention relates to an improved process for preparing (+) (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof, preferably the disodium salt.
This invention relates to novel intermediates useful in preparing (+) (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.
Unless otherwise defined, the term xe2x80x98aromatic ring-fused cyclopentane derivativesxe2x80x99 as used herein, is meant to refer to the racemic compounds of Formula (1): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom;
R1 is 
xe2x80x83where
R3 and R4 are independently H, OH, protected OH, C1-8alkoxy, Br, F, I, Cl, CF3 or
C1-6alkyl and R5 is xe2x80x94OCH2CO2H or xe2x80x94OCH2CH2OH;
R2 is 
where R3 and R4 are as indicated above and
Z is H, OH, or C1-5alkoxy;
or a pharmaceutically acceptable salt thereof.
Preferred among the racemic compounds of Formula (1) are the compounds of Formula (17): 
wherein A, B, C, D, R1, R2 and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
By the term indane carboxylates as used herein is meant the racemic compounds of Formula (2): 
wherein R1, R2 and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
Preferred among the racemic compounds of Formula (2) are the compounds of Formula (18): 
wherein R1, R2 and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
By the term cyclopenteno[b]pyridine derivatives as used herein is meant the racemic compounds of Formula (3): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom; and
R1, R2 and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
Preferred among the racemic compounds of Formula (3) are the compounds of Formula (19): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom; and
R1, R2 and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
In Formula (3) compounds, in Formula (19) compounds and in Formula (1) compounds when one of A, B, C or D is a nitrogen atom, preferably A is nitrogen.
Pharmaceutically acceptable salts of the compounds of Formulas (1), (2), (3), (17), (18) and (19) are formed where appropriate by methods well known to those of skill in the art.
Pharmaceutically acceptable salts of (+) (1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and (+) (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid are formed where appropriate by methods well known to those of skill in the art.
The term (+) (1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid as used herein utilizes standard chemical terminology and refers to a compound of the structure 
The term (+) (1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid ethylene diamine salt (2:1) as used herein utilizes standard chemical terminology and refers to Compound (i) 
The term (+) (1S,2R,3S)-3-(2-carboxymethoxy4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid as used herein utilizes standard chemical terminology and refers to a compound of the structure (Y) 
The term (+) (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid disodium salt as used herein utilizes standard chemical terminology and refers to Compound (g) 
The indane carboxylates of Formula (18) of the current invention are prepared by methods outlined in the Schemes below and in the Examples from compounds of Formula (4): 
where R is H, OH, C1-5alkoxy (preferably n-PrO) or a protected oxy group, such as benzyloxy. Compounds of Formula (4) are known or can be prepared from readily available starting materials by those skilled in the art.
The compounds of Formula (4) can be converted into the compounds of Formula (a) 
where R is as described above, by known methods such as those described in International Publication No. WO 94/25013, published Nov. 10, 1994 in Example 1, section b) on page 20.
By the term xe2x80x98protected oxy groupxe2x80x99 and xe2x80x98protected OHxe2x80x99 as used herein, is meant any conventional blocking group in the art such as described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by Theodora W. Greene, Wiley-Interscience, 1981, New York, provided that such protected oxy groups or such protected OH do not include moieties that render inoperative the presently invented process. A preferred protected oxy group for use herein is benzyloxy. A preferred protected OH for use herein is benzyloxy.
Further, when necessary or desired, R can be converted to a substituent of Z. Reactions to convert R to Z are performed on products of the synthetic pathways disclosed or claimed herein or, where appropriate or preferable on certain intermediates in these synthetic pathways. For example, hydroxyl groups can be converted into C1-5alkoxy groups by alkylation. Protected oxy groups can be deprotected and further reacted to form a substituent of Z.
The present invention provides an improved process for the production of indane carboxylates of Formula (18) as indicated in Schemes 1 to 3 below. 
Scheme 1 outlines formation of indane carboxylates wherein R5 is xe2x80x94OCH2CO2H, preferably the disodium salt, Compound (g). As used in Scheme 1, R3 and R4 are as described in Formula (1) and R is as described in Formula (4). Compounds of Formula (b) are prepared by treating compounds of Formula (a) with a phenol under acidic conditions. Compounds of Formula (c), as the predominately pure enantiomer, are prepared by catalytic hydrogenation of Formula (b) compounds using a chiral catalyst such as [(S)-(xe2x88x92)-2,2xe2x80x2-Bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl]chloro(p-cymene)ruthenium chloride (as used herein, Ru-(S)-(xe2x88x92)-BINAP) at approx. 1-5 atm H2, (Bicyclo[2.2.]hepta-2,5-diene)[2S,3S)-bis(diphenylphosphino)butane]-rhodium(I) perchlorate (as used herein, Rh-(S,S)(Chiraphos)(NBD)ClO4) at approx. 400 psi H2 or preferably, the catalyst prepared by combining [Rh(COD)Cl2 with S,S-Chiraphos, at approx. 180-300 psi. Compounds of Formula (d), as used herein Formula (d) compounds refer to the indicated alcohol diastereomers, are prepared by
combining Formula (c) compounds with the indicated piperonal in an aldol reaction, most preferably by using titanium (IV) chloride in the presence of a base, preferably a hindered amine base, such as N,N-diisopropylethylamine. Formula (d) compounds are treated with an acid to cause Friedel-Crafts alkylation to give the predominately pure enantiomer as Formula (e) compounds. Treatment of Formula (e) compounds with base in the presence of methanol and methyl bromoacetate gives the diester as Formula (f) compounds. Saponification of Formula (f) compounds affords the diacid (preferably Compound Y as used herein) which is treated with sodium hydroxide to give Formula (5) compounds (preferably Compound (g) as used herein). 
Scheme 2 outlines formation of indane carboxylates wherein R5 is xe2x80x94OCH2CH2OH, preferably the ethylene diamine salt (2:1) of Compound (i). As used in Scheme 2, R3 and R4 are as described in Formula (1) and R is as described in Formula (4). Formula (e) compounds from Scheme 1 are treated with base in the presence of methanol to give the phenolester Formula (h) compounds. Alkylation of Formula (h) compounds followed by saponification with lithium hydroxide monohydrate affords the acid (preferably Compound (X) as used herein), which is treated with ethylene diamine to give Formula (6) compounds.
In an alternative aspect of the invention novel intermediates of Formula (c) and Formula (d) are prepared according to Scheme 3 below. 
Scheme 3 outlines a process for the formation of compounds of Formula (c) and compounds of Formula (d). As used in Scheme 3, R3 and R4 are as described in Formula (1), provided that R3 and R4 are not Br, I or Cl, and R is as described in Formula (4). Compounds of Formula (j) can be prepared by treating a compound of the formula HXc, where HXc is as described below, with lithium bis(trimethylsilyl)amide with the subsequent addition of an appropriately substituted (E)-3-phenyl-2-propenoyl chloride compound. Compounds of Formula (1) are prepared by treating cuprous bromide-dimethyl sulphide complex in dimethylsulphide/THF with an appropriate 1-magnesiumbromide-2-benzyloxybenzene compound, followed by the addition of a compound of Formula (j). The Formula (1) compound is treated with palladium on carbon in a hydrogen atmosphere to give a compound of Formula (c).
As used in Scheme 3 compounds of Formula (m) are prepared by treating cuprous bromide-dimethyl sulphide complex in dimethylsulphide/THF with an appropriate 1-magnesiumbromide-2-benzyloxybenzene compound, followed by the addition of a compound of Formula (j), followed by the addition of piperonal. Formula (m) compounds are treated with palladium on carbon in a hydrogen atmosphere to give Formula (d) compounds.
As used in the specification and in the claims the term Xc means a chiral auxiliary. By the term xe2x80x9cchiral auxiliaryxe2x80x9d as used in the specification and in the claims is meant a non-racemic functional group that imparts a diastereoselective reaction at a remote prochiral center of a molecule. Chiral auxiliaries are used herein are formed by reaction with a compound of the formula HXc wherein Xc is as described above. Examples of HXc as used herein include: 8-phenylmenthol (5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexanol, such as described in D. Comins et al. J. Org. Chem., vol. 58, 4656 (1993)), N-substituted bornane-2, 10-sultams (e.g., 10,10-dimethyl-3-thia-4-aza-tricyclo[5.2.1.01.5]decane 3,3-dioxide. such as described in W. Oppolzer J. Am. Chem. Soc., 112 2767 (1990)), preferably, 4-substituted or 4,5-substituted 2-oxazolidinones derived from amino acid derivatives such as phenylglycinol or valinol (e.g., 4-phenyl-2-oxo-oxazolidin-3-yl or 4-isopropyl-2-oxo-oxazolidin-3-yl, respectively, such as described in D. Evans et al. J. Am. Chem. Soc., 109, 6881 (1987) and in D. Evans et al. Tet. Lett., 28, 1123 (1990)) and, most preferably, 4-substituted or 4,5-substituted 2-imidazolidinones derived from compounds such as ephedrine (e.g., 3,4-dimethyl-5-phenyl-2-oxo-imidazolidin-1-yl, such as described in S. E. Drewes, et al. Chem. Ber., 126, 2663 (1993)).
The racemic compounds of Formulas (1), (2) and (3) are prepared according to the methods outlined in Schemes (1) and (2) and in the Examples by substituting a compound of Formula (7): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom and R is H, OH, C1-5alkoxy (preferably n-PrO) or a protected oxy group, such as benzyloxy,
for the compound of formula (4) and by substituting the corresponding achiral catalyst for the chiral catalyst disclosed in Scheme 1 for the preparation of Formula (c) compounds.
Compounds of Formula (7) are known or can be prepared from readily available starting materials by those skilled in the art.
The compounds of Formula (7) can be converted into the compounds of Formula (8) 
where A, B, C, D and R are as described in Formula (7), by known methods such as those described in International Publication No. WO 94/25013, published Nov. 10, 1994 in Example 1, section b) on page 20.
Thus, the compounds of Formula (8) are utilized in Schemes 1 and 2, using an achiral catalyst in the Formula (b) to Formula (c) transformation, to prepare compounds of Formula (1) and intermediates useful in preparing compounds of formula (1). The compounds of Formula (a) are utilized in Schemes 1 and 2, by substituting an achiral catalyst in the Formula (b) to Formula (c) transformation, to prepare compounds of Formula (2) and intermediates useful in preparing compounds of formula (2). The compounds of Formula (8), wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, are utilized in Schemes 1 and 2, using an achiral catalyst in the Formula (b) to Formula (c) transformation, to prepare compounds of Formula (3) and intermediates useful in preparing compounds of formula (3).
The cyclopenteno[b]pyridine derivatives of Formula (19) of the current invention are prepared according the methods outlined in Schemes 1 to 3 and in the
Examples from compounds of Formula (8) wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom. Preferred among Formula (7) and Formula (8) compounds when a nitrogen is present are those wherein A is nitrogen.
The aromatic ring-fused cyclopentane derivatives of Formula (17) of the current invention are prepared according the methods outlined in Schemes 1 to 3 and in the Examples from compounds of Formula (8) wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom. Preferred among Formula (7) and Formula (8) compounds when a nitrogen is present are those wherein A is nitrogen.
Prepared in synthesizing the indane carboxylates of Formula (18), preferably compound (g) and Compound (i), are the novel intermediates of Formula (b): 
wherein R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (g) and Compound (i), are the novel intermediates of Formula (c): 
wherein R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (g) and Compound (i), are the novel intermediates of Formula (d): 
wherein R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (g) and Compound (i), are the novel intermediates of Formula (e): 
wherein R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (g) and Compound (i), are the novel intermediates of Formula (f): 
wherein R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (i), are the novel intermediates of Formula (h): 
wherein R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (g) and Compound (i), are the novel intermediates of Formula 
wherein R is as described in Formula (4).
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (g) and Compound (i), are the novel intermediates of Formula (1): 
wherein R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (g) and Compound (i), are the novel intermediates of Formula (m): 
wherein R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Prepared in synthesizing the aromatic ring-fused cyclopentane derivatives of Formula (1) are the novel intermediates of Formula (9): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Prepared in synthesizing the cyclopenteno[b]pyridine derivatives of Formula (19) are intermediates of Formula (9) where three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the cyclopenteno[b]pyridine derivatives of Formula (19) are the novel intermediates of Formula (10): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the cyclopenteno[b]pyridine derivatives of Formula (19) are the novel intermediates of Formula (11): 
wherein three of A, B, C and D are carbon and one is nitrogen, R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the cyclopenteno[b]pyridine derivatives of Formula (19) are the novel intermediates of Formula (12): 
wherein three of A, B, C and D are carbon and one is nitrogen, R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the cyclopenteno[b]pyridine derivatives of Formula (19) are the novel intermediates of Formula (13): 
wherein three of A, B, C and D are carbon and one is nitrogen, R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the cyclopentenofblpyridine derivatives of Formula (19) are the novel intermediates of Formula (14): 
wherein three of A, B, C and D are carbon and one is nitrogen, R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the cyclopenteno[b]pyridine derivatives of Formula (19) are the novel intermediates of Formula (15): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom and R is as described in Formula (4).
Also prepared in synthesizing the cyclopenteno[b]pyridine derivatives of Formula (19) are the novel intermediates of Formula (16): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom; R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the cyclopenteno[b]pyridine derivatives of Formula (19) are the novel intermediates of Formula (25): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom; R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Prepared in synthesizing the aromatic ring-fused cyclopentane derivatives of Formula (1) are the novel intermediates of Formula (20): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is nitrogen, R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the aromatic ring-fused cyclopentane derivatives of Formula (1) are the novel racemic intermediates of Formula (21): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom; R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the aromatic ring-fused cyclopentane derivatives of Formula (1) are the novel racemic intermediates of Formula (22): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom; R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the aromatic ring-fused cyclopentane derivatives of Formula (1) are the novel racemic intermediates of Formula (23): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom; R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
Also prepared in synthesizing the aromatic ring-fused cyclopentane derivatives of Formula (1) are the novel racemic intermediates of Formula (24): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom; R3 and R4 are as described in Formula (1) and R is as described in Formula (4).
All of the starting materials and reagents used herein are known and readily available or can be easily made from known and readily available reagents.
For example, Rh-(S,S)(Chiraphos)(NBD)ClO4.THF and Ru-(S)-(xe2x88x92)BINAP are obtained from the Aldrich chemical company Milwaukee, Wis.
For example, (E)-3-(3xe2x80x2-propyloxyphenyl)-2-propenoyl chloride, used in Example 3 (i), can be prepared from commercially available 3-hydroxybenzaldehyde by reacting 3-hydroxybenzaldehyde with 1-iodopropane to give 3-propyloxy benzaldehyde. 3-Propyloxy benzaldehyde is then reacted with malonic acid to give the corresponding propenonic acid which is subsequently converted into (E)-3-(3xe2x80x2-propyloxyphenyl)-2-propenoyl chloride by reaction with oxalyl chloride.